EP0469547A2 - 4-Amino-delta4,6-stéroides et leur usage comme inhibiteurs de 5alpha-réductase - Google Patents

4-Amino-delta4,6-stéroides et leur usage comme inhibiteurs de 5alpha-réductase Download PDF

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Publication number
EP0469547A2
EP0469547A2 EP91112795A EP91112795A EP0469547A2 EP 0469547 A2 EP0469547 A2 EP 0469547A2 EP 91112795 A EP91112795 A EP 91112795A EP 91112795 A EP91112795 A EP 91112795A EP 0469547 A2 EP0469547 A2 EP 0469547A2
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EP
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Prior art keywords
alkyl
hydrogen
amino
compound
give
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Granted
Application number
EP91112795A
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German (de)
English (en)
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EP0469547B1 (fr
EP0469547A3 (en
Inventor
Philip M. Weintraub
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Aventis Pharmaceuticals Inc
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Merrell Dow Pharmaceuticals Inc
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Priority claimed from US07/671,555 external-priority patent/US5143909A/en
Priority claimed from US07/720,899 external-priority patent/US5130424A/en
Application filed by Merrell Dow Pharmaceuticals Inc filed Critical Merrell Dow Pharmaceuticals Inc
Publication of EP0469547A2 publication Critical patent/EP0469547A2/fr
Publication of EP0469547A3 publication Critical patent/EP0469547A3/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0011—Unsubstituted amino radicals

Definitions

  • Mammalian steroid 5a-reductase an enzyme present in mammalian tissues including skin, male genitalia and prostate gland, catalyzes the conversion of the steroidal hormone testosterone to the steroidal hormone dihydrotestosterone (17 ⁇ -hydroxy-5 ⁇ -androstan-3-one).
  • Testosterone and dihydrotestosterone (DHT) are both androgenic hormones and they are the primary androgenic steroids in males. These steroids are responsible for the physical characteristics which differentiate males from females. DHT, however, is much more potent than testosterone as an androgen and it acts as an end-organ effector in certain tissues, particularly in mediating growth. Furthermore, the formation of DHT occurs primarily in the target cells themselves as a result of the reduction of testosterone by 5a-reductase.
  • DHT skin responds to androgens and is an active site of androgen metabolism.
  • testosterone is converted to DHT in the skin by the action of 5a-reductase.
  • Testosterone metabolism in the skin may at times be abnormally excessive and have undesirable effects as a result of the DHT formed.
  • DHT is involved in the pathogenesis of acne, including acne vulgaris, as well as other androgen associated conditions [See Price, Arch. Dermatol. 111, 1496 (1975)].
  • Agents which are capable of blocking the formation of DHT from testosterone in skin, such as by inhibiting the activity of 5a-reductase, would therefore be useful in the treatment of acne.
  • the present invention relates a group of compounds which are 4-amino- ⁇ 4,6 -steroids and to the use of these compounds as inhibitors of 5a-reductase. More particularly, the present invention relates to aminosteroid compounds having the following general formula 1 wherein R is hydrogen or C 1 - 4 alkyl; R 1 is C 2 - 6 alkanoyl, -(C 1-6 alkyl)-OZ', -(C 2 - 6 alkyl)-(OZ') 2 or -A-C(O)-Y; Z 1 is hydrogen, C 1-6 alkyl, phenyl-(C 1-4 alkyl), Y'-substituted phenyl)-(C 1-4 alkyl), C 1-6 alkanoyl, benzoyl or Y'-substituted benzoyl wherein Y 1 is methyl, halogen or methoxy; A is absent or is present as an alkylene of 1 to 6 carbon atoms; Y is
  • the various alkyl groups referred to above can be straight or branched-chain and can be exemplified, with the carbon limitations as provided, by methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • the alkyl groups are substituted by two -OZ 1 groups, the two OZ 1 groups are situated on different carbon atoms.
  • Some examples of the two types of HO-substituted alkyl groups referred to above are hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1-methyl-2-hydroxyethyl, 1-hydroxypropyl and 3-hydroxypropyl.
  • etherified R 1 groups i.e., Z 1 is alkyl or phenylalkyl
  • esterified R 1 groups i.e., Z 1 is alkanoyl, benzoyl or substituted benzoyl
  • 2-acetoxy-1-methylethyl and 2-benzoyl-1-methylethyl are 2-acetoxy-1-methylethyl and 2-benzoyl-1-methylethyl.
  • the individual pure optical isomers are each part of this invention.
  • the halogen substituents referred to above are fluorine, chlorine and bromine.
  • the C2 -6 alkanoyl groups referred to above can be straight or branched-chained and can be exemplified by acetyl, propionyl, butyryl, isobutyryl and hexanoyl.
  • the C 1 - 6 alkanoyl, groups can be exemplified similarly and also include formyl.
  • the C 3 - 6 cycloalkyl groups can exemplified by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • -NR 3 R 4 can be exemplified by 1-pyrrolidinyl, 1-piperidinyl or hexahydro-1 H-azepin-1-yl.
  • R 1 is -A-C(O)-Y and A is absent, then the carbonyl function is attached directly to the steroid ring; when A is alkylene of 1 to 6 carbon atoms examples of A are methylene, ethylene, ethylidene, propylene and tetramethylene.
  • R 1 and R 2 are combined as -O-CH 2 CH 2 CH 2 ---, a spiro-tetrahydrofuran structure results.
  • a preferred group of compounds are those in which R 2 is hydrogen and X is (H)(H). Further preferred are those compounds in which R 2 is hydrogen and R 5 is methyl. Still further preferred as potent 5a-reductase inhibitors are those compounds in which R 1 is -C(O)NR 3 R 4 , wherein R 3 and R 4 are each independently hydrogen or C 1 - 6 alkyl.
  • those compounds wherein R 1 is -(C i - 6 alkyl)-OZ 1 wherein Z 1 is defined as above and, particularly, where R 1 is -CH(CH 3 )-CH 2 0Z 1 , are further useful because, in addition to their activity as inhibitors of 5a-reductase, they also inhibit C 17-20 lyase.
  • Acid addition salts of the aforesaid compounds wherein R is hydrogen or C 1 - 6 alkyl, with pharmaceutically acceptable acids are equivalent to the above amines for the purposes of this invention.
  • Illustrative of such salts are the salts with inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric and like acids; with organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids; and with organic sulfonic acids such as methanesulfonic acid and p-
  • the present invention further provides a pharmaceutical composition for treating a patient afflicted with a DHT-mediated disease or condition which comprises an effective 5a-reductase inhibitory amount of a compound of the present invention.
  • the term "patient” refers to a warm-blooded animal, such as a human, which is afflicted with a DHT-mediated disease or condition.
  • DHT-mediated diseases or conditions are those which are associated with elevated androgen activity due to the excessive formation of DHT.
  • DHT-mediated diseases or conditions include acne, acne vulgaris, benign prostatic hypertrophy, androgenic alopecia (common baldness caused by androgen in genetically susceptible men and women), seborrhea and female hirsutism.
  • the present invention further relates to pharmaceutical compositions for the treatment of the particular DHT-mediated diseases and conditions described above.
  • the 4-amino-4,6-diene compounds of the present invention are obtained by the reaction of a 4,5-epoxy compound of the formula 2 wherein R 1 , R 2 , R 5 , X, Z and the dotted lines are defined as above, with sodium azide in an inert solvent such as dimethyl sulfoxide.
  • the reaction is carried out in the presence of a catalytic amount of a strong acid, such as sulfuric acid, with heating at 1000 C. No effort is made to isolate any intermediates but it appears that the epoxide is first opened to give the 4-azido-4-ene.
  • the azido compound loses nitrogen, a putative azirine forms, and this opens to give the desired 4-amino-4,6- diene.
  • the amino compound obtained in this way can be further reacted with an appropriate anhydride to give the corresponding 4-amido compound.
  • anhydride In the case of the formamido compound, mixed formic acetic anhydride, prepared in situ, is used as the anhydride.
  • the 4,5-epoxy compound, used as the starting material of formula 2 above, is itself obtained by the base catalyzed epoxidation of the appropriate corresponding 4-ene using 30% aqueous hydrogen peroxide.
  • a 4,5-epoxy 3-ketone with dichlorodicyanoquinone gives the corresponding il1 epoxide compound.
  • the epoxide product obtained is generally a mixture of the a and ,8-epoxides with the ,8-epoxide being the preponderant product. In some instances, a single isomer is obtained.
  • further reaction of the epoxides with sodium azide as described earlier gives the desired 4-amino-4,6-diene.
  • the starting materials used in the above syntheses are known compounds and/or they can be prepared by standard known procedures.
  • estrone 3-methyl ether can be used as the starting material.
  • the desired substitution at the 17-position is introduced by standard procedures.
  • Birch reduction of the aromatic A-ring followed by acidification gives the corresponding 3-oxo-A4 - 19-norsteroid which is then converted to the epoxide and further reacted as described earlier. Variations in this procedure and the order in which the reactions are carried out are also possible.
  • Treatment of this compound with hydrogen peroxide then gives the corresponding 4,5-epoxide and oxidation of the 20-hydroxy group gives 4,5-epoxy-19-norpregnane-3,20-dione which is then reacted as described earlier.
  • the steroid 4-enes which are used as starting materials above, are themselves known compounds or they can be prepared by known standard chemical procedures.
  • the starting materials containing an ether group in the 17-substituent can be prepared from the corresponding alcohol.
  • a 17-(hydroxyalkyl substituted) steroid-4-en-3-one is first converted to the corresponding 3-methoxysteroid-3,5- diene by reaction with trimethyl orthoformate and a trace of p-toluenesulfonic acid in dioxane as the solvent. Pyridine is used to work up this reaction mixture.
  • the 3-ketone can be protected as the ethylene ketal.
  • the resulting alcohol is then reacted with sodium hydride in dimethylformamide to give the corresponding sodium salt which is then reacted with the appropriate halide, such as methyl iodide or benzyl bromide, to give the corresponding compound containing an ether group as part of the 17-substituent.
  • This ether is then treated with 10% hydrochloric acid, either as part of the general isolation procedure or after isolation of the crude product, to convert the 3-enol ether structure back to the desired steroid-4-en-3-one.
  • the 4-amino-compounds of the present invention in which R 1 is -COOH or a similar acid group can be obtained by the alkaline hydrolysis of the corresponding alkyl ester.
  • Those 4-amino-compounds in which R is C 1 - 4 alkyl are obtained from the corresponding compounds in which R is hydrogen by standard reactions.
  • the compounds of the present invention are useful as 5a-reductase inhibitors. Accordingly, they are useful in the treatment of the various diseases and conditions which would be affected by such inhibitors as described above.
  • the activity of the present compounds as 5a-reductase inhibitors can be demonstrated by the following standard test procedure. Microsomal preparations of the steroid 5a-reductase enzyme (protein) were obtained from human prostate tissue and stored in aliquots. Protein concentration was determined prior to use of the samples.
  • protein steroid 5a-reductase enzyme
  • individual assays for 5a-reductase activity contained 0.1 M phosphate citrate buffer, pH 5.6, 1 mM EDTA, 7 to 22 /1 .g of microsomal protein, 1 mM NADPH, 5 mM glucose-6-phosphate, 1 IU/ml glucose-6-phosphate dehydrogenase, 1,2- 3 H-testosterone, and test compound, dissolved in dimethyl sulfoxide and then diluted in phosphate-citrate buffer to yield a final assay concentration of 0.1% (v/v) dimethyl sulfoxide. The same buffer and the same quantity of dimethyl sulfoxide, without any test compound is used for the control assays. The total assay volume was 100 ⁇ l and assays were performed in duplicate. The reaction was initiated by the addition of the testosterone, and incubated for 30 minutes at 25 C. The assay is linear with time to 30 minutes.
  • testosterone concentration was typically varied from 0.15 ⁇ M (approximately 0.5 K m ) to 10 K m with radioactive label constant at 0.15 ⁇ Ci per assay.
  • the amount of test compound added was varied to provide final concentrations of 1 nM to 100 ⁇ M.
  • the reaction was quenched by the addition of 50 volumes of chloroform:methanol (2:1).
  • the steroids were then extracted and separated by high pressure liquid chromatography and the amounts of testosterone and dihydrotestosterone present were determined to determine the percent conversion of testosterone to dihydrotestosterone and to calculate the 5a-reductase activity.
  • the activity of the test compound was then expressed as the IC 50 , or the concentration of test compound that produced a 50% inhibition of the testosterone conversion.
  • the pharmaceutical composition containing the compounds employed in the present invention can be administered orally, parenterally, for example, intramuscularly and subcutaneously, and topically to a patient in need of treatment.
  • Topical administration is preferred.
  • patient is taken to mean a warm-blooded mammal, for example, primates, human males and females having an acne condition or an oily skin condition in need of treatment.
  • the compounds of the invention can be administered alone or suitably admixed in the form of a pharmaceutical preparation to the patient being treated. The amount of compound administered will vary with the severity of the acne condition or oily skin condition and repetitive treatment may be desired.
  • the amount of compound administered is from 0.001 to 10 mg/kg of body weight per day and preferably from 0.01 to 1.0 mg/kg of body weight per day.
  • Unit dosages for oral or parenteral administration may contain, for example, from 0.2 to 100 mg of the active ingredient.
  • the anti-acne or anti-seborrheic effective amount of the compounds of the invention on a percent basis can vary from 0.001% to 5% and preferably from 0.005% to 1 %.
  • the formulated active ingredient, that is, a compound of the invention can be applied directly to the site requiring treatment or can be applied to the oral or nasal mucosa. Applicator sticks carrying the formulation may be employed in administering the compounds.
  • the pharmaceutical compositions containing the compounds of the invention may be administered in various manners to the patient being treated to achieve the desired effect.
  • patient is taken to mean male warm blooded animals, such as male dogs and human males.
  • the compounds can be administered alone or in combination with one another.
  • the compounds can be administered in the form of a pharmaceutical preparation.
  • the compounds may be administered orally, parenterally, for example, intravenously, intraperitoneally, intramuscularly or subcutaneously, including injection of the active ingredient directly into the prostate. Slow release implants can also be used.
  • the amount of compound administered will vary over a wide range and can be any effective amount.
  • the effective amount of compound administered will vary from about 0.001 to 10 mg/kg of body weight per day and preferably from 0.01 to 1.0 mg/kg of body weight per day.
  • Unit dosages for oral or parenteral administration may contain, for example, from 0.2 to 100 mg of a compound of the invention.
  • These dosage ranges represent the amount of compound that will be effective in reducing the size of the prostate, i.e., the amount of compound effective in treating BPH.
  • the compounds can be administered from onset of hypertrophy of the prostate to regression of the symptoms, and may be used as a preventive measure.
  • the compounds of the present invention may be administered either as individual therapeutic agents or as mixtures with other therapeutic agents. They may be administered alone but are generally administered in the form of pharmaceutical compositions, i.e., mixtures of the active agents with suitable pharmaceutical carriers or diluents. Examples of such compositions include tablets, lozenges, capsules, powders, aerosol sprays, aqueous or oily suspensions, syrups, elixirs and aqueous solutions for injection. The compounds are most preferably administered in oral dosage forms.
  • Oral compositions may be in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g., starch) or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers e.g., lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • lubricants e.g., magnesium
  • Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, flavoring agents, diluents or emulsifying agents.
  • solutions or suspensions of a compound of the present invention with conventional pharmaceutical vehicles may be employed, e.g., as an aqueous solution for intravenous injection or as an oily suspension for intramuscular injection. Procedures for the preparation of compositions as discussed above are described in standard texts, such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • compositions suitable for oral administration which may be employed in practicing the present invention: Mix the active ingredient, lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5%. Screen through a No. 12 mesh screen. Add and mix the following: Compress on a suitable tablet machine to a weight of 0.115 g/tablet. Mix and fill into 50,000 soft gelatin capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
EP91112795A 1990-08-01 1991-07-30 4-Amino-delta4,6-stéroides et leur usage comme inhibiteurs de 5alpha-réductase Expired - Lifetime EP0469547B1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US720899 1985-04-08
US56141090A 1990-08-01 1990-08-01
US561410 1990-08-01
US671555 1991-03-19
US07/671,555 US5143909A (en) 1991-03-19 1991-03-19 Aminosteroids in a method for inhibiting c17-20 lyase
US07/720,899 US5130424A (en) 1990-08-01 1991-07-02 4-amino-delta-4,6-steroids and their use as 5 alpha-reductase inhibitors

Publications (3)

Publication Number Publication Date
EP0469547A2 true EP0469547A2 (fr) 1992-02-05
EP0469547A3 EP0469547A3 (en) 1992-06-03
EP0469547B1 EP0469547B1 (fr) 1996-05-15

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EP91112795A Expired - Lifetime EP0469547B1 (fr) 1990-08-01 1991-07-30 4-Amino-delta4,6-stéroides et leur usage comme inhibiteurs de 5alpha-réductase

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EP (1) EP0469547B1 (fr)
JP (1) JP3021818B2 (fr)
CN (1) CN1031574C (fr)
AT (1) ATE138073T1 (fr)
AU (1) AU642757B2 (fr)
CA (1) CA2048243C (fr)
DE (1) DE69119502T2 (fr)
DK (1) DK0469547T3 (fr)
ES (1) ES2089063T3 (fr)
FI (1) FI102378B1 (fr)
GR (1) GR3020268T3 (fr)
HU (1) HU210042B (fr)
IE (1) IE75199B1 (fr)
IL (1) IL98998A (fr)
NO (1) NO180197C (fr)
NZ (1) NZ239141A (fr)
PT (1) PT98519B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5302589A (en) * 1992-08-07 1994-04-12 Glaxo, Inc. Heterocyclic inhibitors of 5-α-testosterone reductase
US5356935A (en) * 1993-12-13 1994-10-18 Eli Lilly And Company Reduced phenanthrenes
WO1994028010A1 (fr) * 1993-05-25 1994-12-08 Merrell Dow Pharmaceuticals Inc. 4-AMINO-17β-(CYCLOPROPYLOXY)ANDROST-4-EN-3-ONE, 4-AMINO-17β-(CYCLOPROPYLAMINO)ANDROST-4-EN-3-ONE ET COMPOSES CONNEXES UTILES COMME INHIBITEURS DE LYASE C17-20 ET REDUCTASE 5$g(a)
WO1995029932A1 (fr) * 1994-05-02 1995-11-09 Merrell Pharmaceuticals Inc. Procede concernant la preparation de 4-amino-δ4-3-ketosteroides en passant par 4-nitro-δ4-3-ketosteroides
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
US5543406A (en) * 1991-12-20 1996-08-06 Glaxo Wellcome, Inc. Inhibitors of 5-α-testosterone reductase
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
WO2001005364A1 (fr) * 1999-07-15 2001-01-25 The Procter & Gamble Company Composes steroides a base d'azote et leur utilisation pour reguler la pousse des cheveux

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6353939B1 (ja) * 2017-02-15 2018-07-04 横関油脂工業株式会社 油状組成物、その製法、油性基剤および皮膚外用剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2048888A (en) * 1979-05-02 1980-12-17 Richardson Merrell Inc Novel 4-Diazo Steroids Useful as Inhibitors of Testosterone 5 alpha - reductase
GB2171100A (en) * 1985-02-15 1986-08-20 Erba Farmitalia 4-substituted androstendione derivatives and process for their preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2048888A (en) * 1979-05-02 1980-12-17 Richardson Merrell Inc Novel 4-Diazo Steroids Useful as Inhibitors of Testosterone 5 alpha - reductase
GB2171100A (en) * 1985-02-15 1986-08-20 Erba Farmitalia 4-substituted androstendione derivatives and process for their preparation

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543406A (en) * 1991-12-20 1996-08-06 Glaxo Wellcome, Inc. Inhibitors of 5-α-testosterone reductase
US5457098A (en) * 1992-08-07 1995-10-10 Glaxo Inc. 17 βacyl 6 azaandrost-4,6 diazo-4-ene-3-ones
US5302589A (en) * 1992-08-07 1994-04-12 Glaxo, Inc. Heterocyclic inhibitors of 5-α-testosterone reductase
WO1994028010A1 (fr) * 1993-05-25 1994-12-08 Merrell Dow Pharmaceuticals Inc. 4-AMINO-17β-(CYCLOPROPYLOXY)ANDROST-4-EN-3-ONE, 4-AMINO-17β-(CYCLOPROPYLAMINO)ANDROST-4-EN-3-ONE ET COMPOSES CONNEXES UTILES COMME INHIBITEURS DE LYASE C17-20 ET REDUCTASE 5$g(a)
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
US5846976A (en) * 1993-09-17 1998-12-08 Glaxo Wellcome Inc. Androstenone derivative
US5356935A (en) * 1993-12-13 1994-10-18 Eli Lilly And Company Reduced phenanthrenes
WO1995029932A1 (fr) * 1994-05-02 1995-11-09 Merrell Pharmaceuticals Inc. Procede concernant la preparation de 4-amino-δ4-3-ketosteroides en passant par 4-nitro-δ4-3-ketosteroides
US5750744A (en) * 1994-05-02 1998-05-12 Merrell Pharmaceuticals Inc. Process for the preparation of 4-amino- 4-3-ketosteroids via 4-nitro- 4-3-ketosteroids
US5869475A (en) * 1994-05-02 1999-02-09 Merrell Pharmaceuticals, Inc. Certain 3-ketosteroids used to inhibit steroid 5α-reductase
US5965550A (en) * 1994-05-02 1999-10-12 Merrell Pharmaceuticals Inc. Process for the preparation of 4-amino-Δ4 -3-ketosteroids via 4-nitro-Δ4 -3-ketosteroids
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
WO2001005364A1 (fr) * 1999-07-15 2001-01-25 The Procter & Gamble Company Composes steroides a base d'azote et leur utilisation pour reguler la pousse des cheveux

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FI913658A (fi) 1992-02-02
AU642757B2 (en) 1993-10-28
CN1031574C (zh) 1996-04-17
HU210042B (en) 1995-01-30
CA2048243A1 (fr) 1992-02-02
EP0469547B1 (fr) 1996-05-15
NO180197C (no) 1997-03-05
DK0469547T3 (da) 1996-06-10
FI102378B (fi) 1998-11-30
EP0469547A3 (en) 1992-06-03
NO912982L (no) 1992-02-03
GR3020268T3 (en) 1996-09-30
AU8135691A (en) 1992-02-06
IE75199B1 (en) 1997-08-27
FI102378B1 (fi) 1998-11-30
HU912559D0 (en) 1992-01-28
ATE138073T1 (de) 1996-06-15
DE69119502T2 (de) 1996-09-26
DE69119502D1 (de) 1996-06-20
JP3021818B2 (ja) 2000-03-15
ES2089063T3 (es) 1996-10-01
PT98519B (pt) 1999-01-29
IL98998A0 (en) 1992-07-15
IL98998A (en) 1996-01-19
IE912706A1 (en) 1992-02-12
NZ239141A (en) 1994-04-27
CA2048243C (fr) 2003-04-08
NO180197B (no) 1996-11-25
FI913658A0 (fi) 1991-07-31
JPH05320189A (ja) 1993-12-03
HUT59157A (en) 1992-04-28
NO912982D0 (no) 1991-07-31
PT98519A (pt) 1992-06-30
CN1059150A (zh) 1992-03-04

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